Obesity and its associated health disorders and costs are increasing. Fat distribution and the associated risk for developing cardiovascular problems, type-2 diabetes mellitus, certain cancers and other disorders differ for men and women. Men and post-menopausal women have greater risk of developing complications of obesity than younger women. The ventromedial hypothalamus (VMM) is an important regulator of energy homeostasis, and two of its sub-areas, the ventrolateral portion (VL VMM) and the arcuate (ARC) respond to hormones and other signals to control energy intake and expenditure. When large VMM lesions are made that include both the VL VMM and the ARC, animals, especially females, eat more food, burn less energy and become obese. Because both the ARC and the VMN contain dense estrogen receptors (specifically ERa), because reducing estrogen also causes obesity, and because estrogen mediates the sensitivity of the brain to leptin, we hypothesize that when VMM lesions are made, the reduction of estrogen signaling and consequent reduction in leptin signaling are what results in increased body weight. The aims of this proposal follow directly from these observations, and will determine the relative contribution of estrogen signaling through ERa in the regulation of food intake and body weight in the ARC and the VL VMN. Specifically, we will determine if estrogen signaling through ERa in the VL VMN or the ARC is necessary and/or sufficient to regulate food intake and body weight. Our findings will have direct relevance in increasing our understanding of the mechanisms by which estrogen regulates body weight, and this will assist in determining potential therapeutic agents for menopausal women to decrease adiposity and the propensity of diseases associated with obesity.